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Gene Set Enrichment Analysis Identifies Key Innate Immune Pathways in Primary Graft Dysfunction After Lung Transplantation
Author(s) -
Cantu E.,
Lederer D. J.,
Meyer K.,
Milewski K.,
Suzuki Y.,
Shah R. J.,
Diamond J. M.,
Meyer N. J.,
Tobias J. W.,
Baldwin D. A.,
Van Deerlin V. M.,
Olthoff K. M.,
Shaked A.,
Christie J. D.
Publication year - 2013
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.12283
Subject(s) - innate immune system , medicine , immunology , inflammasome , lung transplantation , tlr4 , immune system , transplantation , receptor , gene expression , cd14 , gene , biology , inflammation , genetics
We hypothesized alterations in gene expression could identify important pathways involved in transplant lung injury. Broncho alveolar lavage fluid (BALF) was sampled from donors prior to procurement and in recipients within an hour of reperfusion as part of the NIAID Clinical Trials in Organ Transplantation Study. Twenty‐three patients with Grade 3 primary graft dysfunction (PGD) were frequency matched with controls based on donor age and recipient diagnosis. RNA was analyzed using the Human Gene 1.0 ST array. Normalized mRNA expression was transformed and differences between donor and postreperfusion values were ranked then tested using Gene Set Enrichment Analysis. Three‐hundred sixty‐two gene sets were upregulated, with eight meeting significance (familywise‐error rate, FWER p‐value <0.05), including the NOD‐like receptor inflammasome (NLR; p < 0.001), toll‐like receptors (TLR; p < 0.001), IL‐1 receptor (p = 0.001), myeloid differentiation primary response gene 88 (p = 0.001), NFkB activation by nontypeable Haemophilus influenzae (p = 0.001), TLR4 (p = 0.008) and TLR 9 (p = 0.018). The top five ranked individual transcripts from these pathways based on rank metric score are predominantly present in the NLR and TLR pathways, including IL1β (1.162), NLRP3 (1.135), IL1α (0.952), IL6 (0.931) and CCL4 (0.842). Gene set enrichment analyses implicate inflammasome–mediated and innate immune signaling pathways as key mediators of the development of PGD in lung transplant patients.